We proposed previously that solvation free energy stored in the H-bond network of solvating water (which we refer to as the “solvation field”) is the dominant free energy contribution to both intra- and inter-molecular structure and function under aqueous conditions. Solvation fields can be characterized qualitatively in terms of the inhomogeneous spatial distributions of water occupancy (relative to bulk solvent) across solute surfaces, which range from high occupancy/H-bond enriched to bulk-like to low occupancy/H-bond depleted forms. We proposed in several works that the association and dissociation free energy barriers (to which kon and koff are proportional) consists principally of the desolvation cost of the nascent binding interface, and the cost of re-solvating the dissociating partners, respectively. Previously, we used WATMD to explore the solvation fields of the putative catalytically important structural states of the SARS-COV main protease (Mpro) captured in time-averaged MD trajectories, focusing on the catalytic site (vis-à-vis substrate and inhibitor binding), dimer interface, and other key regions of the protein (ACS Pharmacol. & Translat. Sci. 2019). Here, we have applied WATMD to study the solvation fields of the low molecular weight (LMW) protein degraders thalidomide, lenalidomide and uridine and complementarity thereof to the solvation field of the degrader binding site in a time-averaged cereblon-degrader-CK1α ternary complex (simulated using PDB code = 5FQD) and a cereblon-CK1α binary complex modeled from the same crystal structure (preprint posted in BioRxiv, October 2021). Our results suggest that glue degraders activate cereblon by organizing the substrate binding surface of cereblon and speeding substrate k1, rather than slowing substrate k-1 (thereby questioning the pertinence of the widely used “glue” nomenclature).

Solvation dynamics-powered structure and function of multi-molecular cellular systems exemplified by cereblon-degrader-CK1α ternary complex formation

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.